Pterostilbene / NRF2 Cancer Research Results

PTS, Pterostilbene: Click to Expand ⟱
Features:
Antioxidant found in blueberries, cranberries and grapes.
Pterostilbene (trans-3,5-dimethoxy-40-hydroxystilbene) is a naturally occurring stilbene, found mainly in blueberries and grapes. It is a dimethylated derivative of resveratrol with comparable antioxidant, anti-inflammatory and anticarcinogenic properties [26].
-more bioavailable than resveratrol
-Antioxidant activity: Reduces reactive oxygen species and lipid peroxidation
-Anti-inflammatory: Downregulates pro-inflammatory cytokines- IL-1β, TNF-α, NF-κB
-Amyloid pathology:inhibits Aβ aggregation and promotes clearance- Aβ, APP, BACE1
-Reduces hyperphosphorylation of tau protein
-Inhibits histone deacetylases (HDACs)
-Increases acetylcholine by inhibiting acetylcholinesterase
-Sirtuin activation

Rank Pathway / Axis Cancer Cells Normal Cells Label Primary Interpretation Notes
1 SIRT1 / AMPK metabolic sensing ↑ AMPK; context-dependent SIRT1 modulation ↑ SIRT1 / ↑ AMPK Driver Energy-stress signaling Pterostilbene strongly engages energy-sensing pathways due to high bioavailability
2 PI3K → AKT → mTOR axis ↓ AKT / ↓ mTOR ↔ adaptive suppression Driver Growth and survival inhibition AKT/mTOR suppression explains cytostatic and pro-apoptotic effects in cancer cells
3 Reactive oxygen species (ROS) ↑ ROS (mild, dose-dependent) ↓ ROS / buffered Conditional Driver Biphasic redox modulation More balanced redox profile than resveratrol; weaker pro-oxidant behavior
4 Mitochondrial integrity / intrinsic apoptosis ↓ ΔΨm; ↑ caspase activation ↔ preserved Secondary Execution of apoptosis Mitochondrial apoptosis follows metabolic and redox stress
5 NF-κB signaling ↓ NF-κB activation ↓ inflammatory NF-κB tone Secondary Suppression of inflammatory survival programs NF-κB inhibition contributes to anti-invasive and chemosensitizing effects
6 Cell cycle regulation ↑ G1 or G2/M arrest ↔ spared Phenotypic Cytostatic growth control Cell-cycle arrest reflects upstream metabolic and signaling effects
7 NRF2 antioxidant response NRF2 (adaptive) NRF2 (protective) Adaptive Redox compensation NRF2 activation contributes to stress buffering rather than primary cytotoxicity


NRF2, nuclear factor erythroid 2-related factor 2: Click to Expand ⟱
Source: TCGA
Type: Antiapoptotic
Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response.
-One way to estimate Nrf2 induction is through the expression of NQO1.
NQO1, the most potent inducer:
SFN 0.2 μM,
quercetin (2.5 μM),
curcumin (2.7 μM),
Silymarin (3.6 μM),
tamoxifen (5.9 μM),
genistein (6.2 μM ),
beta-carotene (7.2μM),
lutein (17 μM),
resveratrol (21 μM),
indol-3-carbinol (50 μM),
chlorophyll (250 μM),
alpha-cryptoxanthin (1.8 mM),
and zeaxanthin (2.2 mM)

1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects.
2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death.
3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress

-In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies.
-Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate.
Decreased Nrf2 expression: Skine, Liver, Pancreatic.
-Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer
- "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1.

Nrf2 Inhibitors and Activators
Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin
Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api
- potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany

Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue.
– In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis.
– In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity.
– This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming.
– Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies.
– High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types.
– While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression.

NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS).
-Brusatol: most cited natural inhibitors of Nrf2.
-Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent.
-Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent .
-Oridonin:
-Wogonin: although its effects might be cell‑ and dose‑specific.
- Withaferin A

Scientific Papers found: Click to Expand⟱
4693- PTS,    Pterostilbene in the treatment of inflammatory and oncological diseases
BioAv↑, *Inflam↓, *antiOx↑, AntiTum↑, BBB↑, Half-Life↝, *ROS↓, *NRF2↑, *NQO1↑, *HO-1↑, PTEN↑, miR-19b↓, TumCCA↑, ER Stress↑, PERK↑, ATF4↑, CHOP↑, Ca+2↝, EMT↓, NF-kB↓, Twist↓, Vim↓, E-cadherin↑, ChemoSen↑, toxicity∅, toxicity↝,
4703- PTS,  RES,    Pterostilbene and resveratrol: Exploring their protective mechanisms against skin photoaging - A scoping review
- NA, Nor, NA
*AntiAge↑, *eff↑, *Inflam↓, *AntiCan↑, *ROS↓, *Catalase↑, *GSR↑, *HO-1↑, *NAD↑, *NQO1↑, *SOD↑, *NRF2↑,
5033- PTS,    Involvement of the Nrf2 Pathway in the Regulation of Pterostilbene-Induced Apoptosis in HeLa Cells via ER Stress
- in-vitro, Cerv, HeLa
ER Stress↑, ROS↑, NRF2↑, TumCP↓, GSH/GSSG↓,
3924- PTS,    Effect of resveratrol and pterostilbene on aging and longevity
- Review, AD, NA - Review, Stroke, NA
*antiOx↓, *ROS↑, *SOD↑, *GSH↑, *NRF2↑, *MDA↓, *HNE↓, *Inflam↓, *MAPK↓, *IL6↓, *TNF-α↓, *HO-1↑, *cardioP↑, *neuroP↑, *CRM↑, *NLRP3↓,
3927- PTS,    Effects of Pterostilbene on Cardiovascular Health and Disease
- Review, AD, NA - Review, Stroke, NA
*Inflam↓, *antiOx↑, *BioAv↑, *toxicity↓, *NADPH↓, *ROS↓, *Catalase↑, *GSH↑, *SOD↑, *TNF-α↓, *IL1β↓, *IL4↓, *MMPs↓, *COX2↓, *MAPK↝, *NF-kB↓, *IL8↓, *MCP1↓, *E-sel↓, *lipid-P↓, *NRF2↑, *PPARα↑, *LDL↓, other↓,
3929- PTS,    New Insights into Dietary Pterostilbene: Sources, Metabolism, and Health Promotion Effects
- Review, Var, NA - Review, Arthritis, NA
*NRF2↑, *BioAv↑, *ROS↓, *Inflam↓, *HO-1↑, *SOD↑, *Catalase↑, *GPx↑, *lipid-P↓, *hepatoP↑, *neuroP↑, *iNOS↓, *COX2↓, TumMeta↓, SOD2↓, ROS↑, TumCI↓, TumCG↓, HDAC1↓, PTEN↑, BP↓, *GutMicro↑,

Showing Research Papers: 1 to 6 of 6

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 6

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress

GSH/GSSG↓, 1,   NRF2↑, 1,   ROS↑, 2,   SOD2↓, 1,  

Transcription & Epigenetics

other↓, 1,  

Protein Folding & ER Stress

CHOP↑, 1,   ER Stress↑, 2,   PERK↑, 1,  

Cell Cycle & Senescence

TumCCA↑, 1,  

Proliferation, Differentiation & Cell State

EMT↓, 1,   HDAC1↓, 1,   PTEN↑, 2,   TumCG↓, 1,  

Migration

Ca+2↝, 1,   E-cadherin↑, 1,   miR-19b↓, 1,   TumCI↓, 1,   TumCP↓, 1,   TumMeta↓, 1,   Twist↓, 1,   Vim↓, 1,  

Angiogenesis & Vasculature

ATF4↑, 1,  

Barriers & Transport

BBB↑, 1,  

Immune & Inflammatory Signaling

NF-kB↓, 1,  

Drug Metabolism & Resistance

BioAv↑, 1,   ChemoSen↑, 1,   Half-Life↝, 1,  

Clinical Biomarkers

BP↓, 1,  

Functional Outcomes

AntiTum↑, 1,   toxicity↝, 1,   toxicity∅, 1,  
Total Targets: 31

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress

antiOx↓, 1,   antiOx↑, 2,   Catalase↑, 3,   GPx↑, 1,   GSH↑, 2,   GSR↑, 1,   HNE↓, 1,   HO-1↑, 4,   lipid-P↓, 2,   MDA↓, 1,   NQO1↑, 2,   NRF2↑, 5,   ROS↓, 4,   ROS↑, 1,   SOD↑, 4,  

Core Metabolism/Glycolysis

CRM↑, 1,   LDL↓, 1,   NAD↑, 1,   NADPH↓, 1,   PPARα↑, 1,  

Cell Death

iNOS↓, 1,   MAPK↓, 1,   MAPK↝, 1,  

Migration

E-sel↓, 1,   MMPs↓, 1,  

Immune & Inflammatory Signaling

COX2↓, 2,   IL1β↓, 1,   IL4↓, 1,   IL6↓, 1,   IL8↓, 1,   Inflam↓, 5,   MCP1↓, 1,   NF-kB↓, 1,   TNF-α↓, 2,  

Protein Aggregation

NLRP3↓, 1,  

Drug Metabolism & Resistance

BioAv↑, 2,   eff↑, 1,  

Clinical Biomarkers

GutMicro↑, 1,   IL6↓, 1,  

Functional Outcomes

AntiAge↑, 1,   AntiCan↑, 1,   cardioP↑, 1,   hepatoP↑, 1,   neuroP↑, 2,   toxicity↓, 1,  
Total Targets: 45

Scientific Paper Hit Count for: NRF2, nuclear factor erythroid 2-related factor 2
6 Pterostilbene
1 Resveratrol
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:139  Target#:226  State#:%  Dir#:2
wNotes=0 sortOrder:rid,rpid

 

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